A solid pharmaceutical product, such as a tablet or capsule, is generally composed of a mixture of active ingredient(s) and excipient(s) (i.e., pharmacologically inactive ingredients). Predictable and reproducible drug absorption from a solid dosage form after oral administration depends on several factors such as the release of the drug substance from the drug product and the dissolution or solubilization of the drug under physiological conditions. In case of drugs such as orodispersible allergen vaccines, it is very important that the dosage form disperse instantaneously upon contact with the saliva of the oral cavity in order to ensure that as much as possible of the active ingredient is presented to the mucosa of the oral cavity.
Because of the critical nature of the release of the drug substance from the drug product and the dissolution or solubilization of the drug, dissolution testing is often relevant to the prediction of in-vivo performance of a drug. Since in-vivo bio-studies tend to be expensive and time consuming, and ethical concerns can limit the desirability of these studies in humans, in-vitro drug dissolution tests are desirable as a low-cost and low-risk alternative.
Drug approving authorities such as EMEA and the FDA often require pharmaceutical companies to determine the drug release characteristics of any new pharmaceutical product in order to obtain approval and such testing can also be required as an on-going quality parameter.
Various protocols have been developed for conducting such in-vitro dissolution tests, and are routinely used for both product development and quality assurance. Often, drug dissolution testing is conducted using recommended compendial methods and apparatus, such as the U.S. Pharmacopoeia and the European Pharmacopoeia e.g. USP 28 <711> and EP 5.0, 2.9.3. Dissolution profiles are often used by the approving authorities such as FDA and EMEA for accepting products, waive bioequivalence requirements and support requests for other bioequivalence requirements than the recommended. Dissolution media typically used in such tests are e.g. phosphate buffers, water and citrate buffers. Four different types of dissolution apparatus, based on different stirring methods are commonly available commercially and have compendial recognition. These apparatus are known as: paddle, basket, flow-through, and reciprocating cylinder. Of the four types of apparatus, the paddle apparatus is the most commonly used. Several standard paddle-type drug dissolution testing apparatus are known, such as those manufactured by Varian Inc., Distek Inc. and others. While exact protocols and apparatus vary, all drug dissolution test methods involve placing the pharmaceutical product into an aqueous dissolution medium (e.g. water and/or buffers), and applying some form of agitation to the dissolution medium in order to promote disintegration and dissolution of the product under test.
Blanco-Príeto et al., Int. J. Pharm. 184 (2), 1999, 243-250, disclose a test medium for studying the release kinetics of a somatostatin analogue from poly(D,L-lactide-co-glycolide) microspheres. The test media were phosphate buffer saline (PBS) in different pH and molarities, and with or without 1, 5 and 10% bovine serum albumin (BSA) or 1, 4 and 10% human serum albumin (HSA). The concentration of the somatostatin analogue was subsequently determined by HPLC.
The immune system is accessible through i.a. the oral cavity and oromucosal, e.g. sublingual administration of allergens is a known route of administration. It is as for most pharmaceuticals very important to administer a correct dosage of an allergen to a patient. The dissolution testing conditions should be based on the physicochemical characteristics of the drug substance and the environmental conditions the dosage form might be exposed to after oral administration. Many of the known dissolution media are developed for oral formulations intended to be swallowed and absorbed through the gastrointestinal tract and are not suitable for pharmaceutical products intended to be dispersed in the mouth such as under the tongue and act in the oral cavity.
Furthermore, proteins are often unstable in solution, especially when they are in low concentration and may denaturate with adsorption to surfaces such as glass surfaces as a result.
The active ingredient in an allergen tablet is a mixture of proteins some of which may have a low stability in solution, chemical as well as physical, and stability considerations are therefore of great importance for the proper choice of dissolution medium. Commonly used dissolution media are not suitable for dissolution of solid dosage forms containing proteins such as allergens in low concentration due to physical instability or denaturation in solution.
A dissolution medium which enables reproducible dissolution of protein containing products, which is pharmaceutically relevant and which overcomes the problems with adsorption to the surfaces remains therefore highly desirable.